The candidate is board certified in Cardiology and Cardiac Electrophysiology. He has an extensive background in cardiovascular research including a Doctorate in Pharmacology. He proposes to use his very strong background in Clinical Pharmacology and Clinical Electrophysiology to develop a program to elucidate the molecular basis of atrial fibrillation (AF). Abundant data from Darbar and others supports the underlying hypothesis that genetic factors play a prominent role in the development of AF and its response to therapy. The resources for the candidate to develop as a clinical investigator and to attack this hypothesis are in place. Through this K23 award, the candidate seeks to obtain formal training in human molecular genetics, while developing a vigorous research program combining patient-oriented research and laboratory-based studies. The highly supportive environment at Vanderbilt University coupled to a formal mentoring process, makes it likely the candidate will develop as a nationally and internationally recognized expert in this area. AF, the most common sustained arrhythmia, affects over 2 million Americans and is associated with significant morbidity and mortality. Current therapies for AF are limited partly due to poor understanding of fundamental mechanisms in disease pathogenesis. Identification of gene(s) responsible for AF will provide important insight into the molecular pathways that contribute to AF. There is growing recognition that AF can be a heritable disorder with loci mapped to chromosomes 10 and 6 and an AF-causing mutation in KCNQ1 gene. The candidate has identified multiple extended families with familial AF. The first aim of this study is to identify and phenotype kindreds with familial AF. The second aim is to genotype families with known/candidate AF genes. Most AF is considered secondary to other conditions such as hypertension, hyperthyroidism, cardiomyopathy or valvular disease; however, a substantial minority of patients without obvious cause are said to have "lone" AF. Preliminary data from Darbar suggest that patients presenting with lone AF in the 4/5 th decades of life have a genetic basis for their condition. Hence, the third aim of this study is investigate the role of genetic factors in patients and their first degree relatives with lone AF while identifying larger kindreds suitable for positional cloning approaches. With this approach, the candidate has identified over 90 probands with lone AF including multiple extended families. This complementary strategy of evaluating individuals and families will enhance our understanding of the molecular pathways of AF and identify novel therapeutic strategies for the prevention and treatment of this common and morbid condition.